Opioid Abuse, Opioid Dependence
Conditions
Keywords
prescription opioid abuse, pain, opioid withdrawal, oxycodone, ibudilast
Brief summary
Opioid drugs increase glial cell activation which may be related to the abuse liability of opioid drugs. Data supporting this hypothesis have demonstrated that glial cell attenuators decrease the positive rewarding aspect of opioids in laboratory animals. Ibudilast (MN-166, formerly AV411) is a compound that inhibits the activation of glia. Recent preclinical studies demonstrate that while ibudilast increases the analgesic effects of opioids, it decreases the rewarding effects of such drugs. It has also been shown that ibudilast suppresses morphine-induced release of dopamine, a primary neurotransmitter involved in the rewarding and reinforcing effects of abused drugs. Additionally, we recently found that ibudilast decreases subjective symptoms of opioid withdrawal in opioid dependent humans during detoxification. Therefore, the primary aim of this 6-7 week inpatient study is to investigate the ability of MN-166 to dose-dependently alter the reinforcing, analgesic, subjective, performance, and physiological effects of oxycodone, a commonly abused prescription opioid. This study includes a 10-day morphine taper phase, followed by two study phases (approximately 18 days each) with daily active ibudilast and placebo administration, respectively. After the detoxification phase, participants are randomized to receive placebo or MN-166, and then be stabilized on the medication. Thereafter, participants will complete laboratory sessions. Subsequently, during Phase 2, participants will cross over to the other treatment arm, stabilize, and complete laboratory sessions.
Detailed description
Opioid drugs increase glial cell activation and consequent cytokine release. These changes in glial cell activation may be related to the abuse liability of opioid drugs including heroin and prescription opioids. Data supporting this hypothesis have demonstrated that glial cell attenuators decrease the positive rewarding aspect of opioids in laboratory animals. Ibudilast (MN-166, formerly AV411) is a compound that inhibits the activation of glia and thereby inhibits the release of cytokines. Recent preclinical studies demonstrate that while ibudilast increases the analgesic effects of opioids, it decreases the rewarding effects of such drugs. It has also been shown that ibudilast suppresses morphine-induced release of dopamine, a primary neurotransmitter involved in the rewarding and reinforcing effects of abused drugs. Additionally, we recently found that ibudilast decreases subjective symptoms of opioid withdrawal in opioid dependent humans during detoxification. Therefore, the primary aim of this 6-7 week inpatient study is to investigate the ability of MN-166 to dose-dependently alter the reinforcing, analgesic, subjective, performance, and physiological effects of oxycodone, a commonly abused prescription opioid. A secondary aim is to verify the ability of the drug to decrease opioid withdrawal symptoms during the initial inpatient detoxification. This inpatient study includes a detoxification and two 18-day study phases. Upon study initiation, participants are tapered with morphine before study phase 1 starts, when they are randomized to receive placebo or 50 mg MN-166 BID (po at 0800 and 2000 hr), and then switched and stabilized on the medication. Thereafter, participants will complete 6 laboratory sessions over 9-10 days. Subsequently, during Phase 2, participants will cross over to the other study arm (Pbo to MN-166 or MN-166 to Pbo), stabilize, and complete again 6 laboratory sessions. Days 1-10 of the study include a morphine taper, while each of the two subsequent study phases consist of a 7-8-day medication switch and stabilization phase, followed by 6 laboratory sessions over the next 9-10 days (3 sample sessions and 3 choice sessions). During sample sessions, participants will receive one dose of oxycodone (0, 15, or 30 mg/70 kg, PO) that will be available during the choice session the following day. At least 72 hrs after the previous sample session, the second sample session will be completed, followed by a choice session the next day. And then at least 72 hrs after the second sample session, the third and final sample session will be completed, followed by the final choice session the next day. The analgesic, subjective, performance, and physiological effects of oxycodone will be measured. During the choice session, a drug versus money self-administration paradigm will be employed, and the progressive ratio that is completed for drug and/or money will be measured. We hypothesize that MN-166 will dose-dependently decrease oxycodone self-administration and positive subjective responses while increasing the analgesic effects of the drug. A secondary additional objective is to collect exploratory information on potential predictors of prescription opioid self-administration including genetic polymorphisms, neurocognitive functioning, and response to stress. Blood samples will be collected to measure various genetic markers hypothesized to contribute to opioid drug effects (e.g., OPRM1, OPRD1, OPRK1, PENK, PDYN, DRD2, CYP3A4, and CYP2D6 genes). Performance on neurocognitive tasks and physiological response to the Trier Social Stress Test will be assessed in all participants.
Interventions
DRUGMN-166 (50 mg) First
In this arm of the study participants were first maintained on 50 mg MN-166 BID for approximately 14 days, and were then switched onto placebo maintenance. The subjective and analgesic effects of Oxycodone (0 mg, 15 mg and 30 mg) were tested under each of the two maintenance conditions (Placebo & MN-166).
DRUGPlacebo First
This arm of the study participants were first maintained on placebo for approximately 14 days, and were then switched onto 50mg MN-166 BID maintenance. . The subjective and analgesic effects of Oxycodone (0 mg, 15 mg and 30 mg) were tested under each of the two maintenance conditions (Placebo & MN-166).
Sponsors
National Institute on Drug Abuse (NIDA)
MediciNova
New York State Psychiatric Institute
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Adults between the ages of 21 and 55 * Current opioid dependence according to DSM-IV criteria * currently not seeking treatment
Exclusion criteria
* Female patients that are currently pregnant, or breastfeeding. Lack of effective birth control. * Participants who have a positive history of neurological illness (including epilepsy) or those who have received anticonvulsant therapy during the past 5 years. * Liver disease requiring medication or medical treatment, and/or aspartate or alanine aminotransferase levels greater than 3 times the upper limit of normal. * Gastrointestinal or renal disease that would significantly impair absorption, metabolism or excretion of study drug, or require medication or medical treatment. * Neurological or psychiatric disorders including psychosis, bipolar disorder, organic brain disease, any seizure history or other disorders that require treatment or that could make study compliance difficult. * Positive tuberculosis (PPD) TB skin test, clinical history, and chest X-ray indicative of active tuberculosis. (Individuals with a positive PPD test and negative chest X-ray who are not symptomatic for tuberculosis, and do not require antituberculosis therapy will be eligible to participate. Participants will be asked if they ever tested positive for tuberculosis. If so, they will not be given a PPD and chest X-ray and clinical history will be used for evaluation purposes). * Presence or positive history of severe medical illness or cardiovascular disease or heart abnormality, such as low hemoglobin (Hb \< 13 gm/dL in males, Hb \< 11 gm/dL in females) with evidence of acute or chronic blood loss, or BP \> 140/90. * Participants on any current psychoactive prescription medications that may interfere with the study measures. * Current physical dependence on any substance, other than opioids, nicotine or caffeine (ex., methadone, benzodiazepines, LAAM, marijuana, alcohol, etc.). * Participants for whom detoxification is not clinically recommended such as those with a significant history of overdose following detoxification. * Participation in an investigational drug study within the past 3 months. * Hypersensitivity to any of the medications used in this study. * Current (within the last 3 months) chronic pain. * Platelet and white blood cell count that are not within the normal range (platelet = 120 x103/μl -400 x103/μl; WBC= 3.5 x106/μl -10.8x106/μl). * Use of Theophylline (PDE-3 inhibitor) or Roflumilast (PDE-4 inhibitor).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Drug Self-administration Breakpoint | 42 days | Participants are allowed to perform an operant task (click on a mouse) in order to receive a dose drug under investigation (oxycodone dose 0 mg, 15 mg, or 30 mg). The drug breakpoint is the maximum number of responses (mouse clicks) the participant was willing to make to receive the drug. Within the context of abuse liability studies, larger breakpoints represent greater abuse potential of a drug. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Positive Subjective Effects to Oxycodone | 42 days | Participants are shown a 100-mm line and asked to indicate on that line the extent to which they agree with the descriptor of the drug effect such as Liking/Liked the Drug. On this visual analog scale participants were instructed that the Left/ 0 mm point on the line represents not at all, while the right/100 mm point represents Extremely. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Pain Intensity | 42 days | 15-item shortened form of the McGill Pain Questionnaire (Melzack, 1987) that is used to assess the sensory and affective dimensions of the pain experienced Participants describe their experience of pain by choosing among a series of possible answers (None \[score=1\], Mild \[score=2\], Moderate \[score=3\], or Severe \[score=4\]). They were asked to describe the pain as Throbbing, Shooting, Stabbing, Sharp, Cramping, Gnawing, Hot-Burning, Aching, Heavy, Tender, Splitting, Tired-Exhausting, Sickening, Fearful, and Punishing-Cruel. Scores were added across all 15 items to generate a sum score, which ranged between 15 and 60. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| MN-166 (Formerly AV411) Patient began maintenance on active medication first (MN-166, formerly AV411) prior to maintenance on placebo. The subjective and analgesic effects of Oxycodone (0 mg, 15 mg and 30 mg) were tested under each of the two maintenance conditions (MN-166, then placebo). Data are only from participants who completed both phases of the study. | 3 |
| Placebo Patient began maintenance on placebo medication prior to maintenance active medication (MN-166, formerly AV411). The subjective and analgesic effects of Oxycodone (0 mg, 15 mg and 30 mg) were tested under each of the two maintenance conditions (Placebo, then MN-166). Data are only from participants who completed both phases of the study. | 8 |
| Total | 11 |
Baseline characteristics
| Characteristic | MN-166 (Formerly AV411) | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 41.3 years STANDARD_DEVIATION 10.8 | 49.5 years STANDARD_DEVIATION 1.7 | 42.2 years STANDARD_DEVIATION 8.7 |
| Region of Enrollment United States | 3 participants | 8 participants | 11 participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 3 Participants | 7 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 16 |
| other Total, other adverse events | 3 / 12 | 7 / 16 |
| serious Total, serious adverse events | 0 / 12 | 0 / 16 |
Outcome results
Primary
Drug Self-administration Breakpoint
Participants are allowed to perform an operant task (click on a mouse) in order to receive a dose drug under investigation (oxycodone dose 0 mg, 15 mg, or 30 mg). The drug breakpoint is the maximum number of responses (mouse clicks) the participant was willing to make to receive the drug. Within the context of abuse liability studies, larger breakpoints represent greater abuse potential of a drug.
Time frame: 42 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MN-166 + Oxy 0 mg | Drug Self-administration Breakpoint | 347 Clicks on a computer mouse | Standard Error 360 |
| MN-166 + Oxy 15 mg | Drug Self-administration Breakpoint | 363 Clicks on a computer mouse | Standard Error 180 |
| MN-166 + Oxy 30 mg | Drug Self-administration Breakpoint | 1472 Clicks on a computer mouse | Standard Error 763 |
| Placebo + Oxy 0 mg | Drug Self-administration Breakpoint | 43 Clicks on a computer mouse | Standard Error 25 |
| Placebo + Oxy 15 mg | Drug Self-administration Breakpoint | 1650 Clicks on a computer mouse | Standard Error 948 |
| Placebo + Oxy 30 mg | Drug Self-administration Breakpoint | 2459 Clicks on a computer mouse | Standard Error 1184 |
Secondary
Positive Subjective Effects to Oxycodone
Participants are shown a 100-mm line and asked to indicate on that line the extent to which they agree with the descriptor of the drug effect such as Liking/Liked the Drug. On this visual analog scale participants were instructed that the Left/ 0 mm point on the line represents not at all, while the right/100 mm point represents Extremely.
Time frame: 42 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MN-166 + Oxy 0 mg | Positive Subjective Effects to Oxycodone | .8 units on a scale | Standard Deviation 5.6 |
| MN-166 + Oxy 15 mg | Positive Subjective Effects to Oxycodone | 10.9 units on a scale | Standard Deviation 23.9 |
| MN-166 + Oxy 30 mg | Positive Subjective Effects to Oxycodone | 24.2 units on a scale | Standard Deviation 35.1 |
| Placebo + Oxy 0 mg | Positive Subjective Effects to Oxycodone | .9 units on a scale | Standard Deviation 3.4 |
| Placebo + Oxy 15 mg | Positive Subjective Effects to Oxycodone | 15.5 units on a scale | Standard Deviation 27.2 |
| Placebo + Oxy 30 mg | Positive Subjective Effects to Oxycodone | 22.7 units on a scale | Standard Deviation 36.9 |
Other Pre-specified
Pain Intensity
15-item shortened form of the McGill Pain Questionnaire (Melzack, 1987) that is used to assess the sensory and affective dimensions of the pain experienced Participants describe their experience of pain by choosing among a series of possible answers (None \[score=1\], Mild \[score=2\], Moderate \[score=3\], or Severe \[score=4\]). They were asked to describe the pain as Throbbing, Shooting, Stabbing, Sharp, Cramping, Gnawing, Hot-Burning, Aching, Heavy, Tender, Splitting, Tired-Exhausting, Sickening, Fearful, and Punishing-Cruel. Scores were added across all 15 items to generate a sum score, which ranged between 15 and 60.
Time frame: 42 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MN-166 + Oxy 0 mg | Pain Intensity | 30 units on a scale | Standard Error 3 |
| MN-166 + Oxy 15 mg | Pain Intensity | 25 units on a scale | Standard Error 1 |
| MN-166 + Oxy 30 mg | Pain Intensity | 26 units on a scale | Standard Error 2 |
| Placebo + Oxy 0 mg | Pain Intensity | 31 units on a scale | Standard Error 2 |
| Placebo + Oxy 15 mg | Pain Intensity | 29 units on a scale | Standard Error 2 |
| Placebo + Oxy 30 mg | Pain Intensity | 27 units on a scale | Standard Error 2 |